A team of scientists from the Virginia Tech Carilion Research Institute and Vanderbilt University have explained how a genetic mutation gives rise to Von Hippel-Lindau syndrome, which causes tumors to grow in several organs.

Their study was published recently in JCI Insight, a journal of the American Society for Clinical Investigation.

Von Hippel-Lindau syndrome is a rare disease, affecting about one in every 36,000 people, according to the National Institutes of Health. People with the disorder have an increased risk for developing cancer, but a main concern is on the syndrome’s characteristic benign growths.

The benign lesions that occur in this disease are made of newly formed blood vessels that can cause serious complications in the retina, brain, spinal cord, and the inner ear.

“These growths have the most unusual vasculature I’ve ever seen. It’s chaotic and mispatterned, and as soon as I saw it, I knew I wanted to figure out how this mutation could lead to such disorganized vessels,” said John Chappell, an assistant professor at the VTCRI’s Center for Heart and Regenerative Medicine and a senior author on the paper. “Seven years after we began this study, we have a much better understanding of how the genetic mutations that cause Von Hippel-Lindau syndrome disrupt vascular patterning and maturation, and how those processes might impact more common complications, such as cancer.”

Chappell is also an assistant professor in the department of biomedical engineering and mechanics in Virginia Tech’s College of Engineering. Before starting his laboratory at VTCRI, Chappell worked at the University of North Carolina at Chapel Hill with Kimryn Rathmell, who is now the director of the division of hematology and oncology and the Cornelius Abernathy Craig Chair of the department of medicine at the Vanderbilt University Medical Center.

Rathmell had developed a mouse model to study conditionally induced mutations, similar to the mutations that lead to Von Hippel-Lindau syndrome in humans.

“We have known for a long time that patients with Von Hippel-Lindau syndrome display variable features of the disease,” Rathmell said. “These animal models were constructed to allow us to explore the range of effects caused by different types of mutations occurring in the same gene.”

Rathmell was particularly interested in how the mutated gene led vessels to remodel into tumors, especially considering that the healthy gene was actually responsible for suppressing tumors. The team found that the mutation severely reduced how the vessels branched out in later development, but also it significantly accelerated the maturation of arterial vessels, especially in the cells that line the blood vessels called pericytes. These cells wrap around the endothelial cells that line blood vessels and help regulate blood flow and maintain vessel integrity and stability.

“We conducted a large genetic screen and found that gene expression changed within several key pathways,” Chappell said, noting one pathway called Notch, which regulates a variety of cell processes and plays a key role in the development of the nervous and cardiovascular systems, and another pathway involved primarily in pericytes. “We suspected this change, but the extent of it was surprising. Von Hippel-Lindau mutations not only cause abnormal blood vessel growth, but they also cause new and existing vasculature to remodel in unusual ways.”

In health, the Notch pathway helps cells communicate and regulates growth and differentiation of neurons, as well as of vascular cells during development. The Von Hippel-Lindau protein helps the body sense oxygen levels, which cues other actions, including how vessels grow and branch out, in part through crosstalk with the Notch pathway. The mutated gene confuses those signals, disrupting the oxygen-sensing abilities, and the vasculature suffers.

“This pathway may be a therapeutic target, and we’re continuing to study it,” Chappell said. “Our hope is to inform the clinical management of Von Hippel-Lindau syndrome, and perhaps aid in the development of new therapeutics.”

This work was funded by National Institutes of Health, VTCRI, and the University of North Carolina Lineberger Comprehensive Cancer Center.

In addition to the Vanderbilt and University of North Carolina teams, other VTCRI collaborators from Chappell’s laboratory include Laura Beth Payne, a postdoctoral associate; Morgan Julian, a student at the Virginia Tech Carilion School of Medicine; Sarah Taylor, a research associate and Chappell’s laboratory manager; Huaning Zhao, a graduate student in Virginia Tech’s department of biomedical engineering and mechanics; and Jordan Darden, a graduate student in Virginia Tech’s translational biology, medicine, and health graduate program.

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